The goal of this proposal is to determine the roles of beta-1 and beta-2 adrenergic receptors in depression and the mediation of antidepressant effects. To address this issue, three lines of investigation are proposed. First, it will be determined whether mice deficient in beta-1, beta-2, or both beta-1 and beta-2 adrenergic receptors display depressive-like behavior. This will be accomplished by testing these three genotypes of mice and wild-type controls in behavioral models sensitive to proven antidepressant drugs, including forced-swim and tail-suspension tests. Second, it will be determined whether administration of beta adrenergic agonists or antidepressant drugs produces antidepressant-like effects in mice deficient in beta-1, beta-2, or both beta-1 and beta-2 adrenergic receptors. This will be accomplished by testing the effects of the non-selective beta adrenergic receptor agonist isoproterenol, selective beta-1and beta-2 adrenergic agonists dobutamine and clenbuterol, respectively, and the antidepressants desipramine and fluoxetine on forced-swim behavior in the gene knockout mice and wild-type controls. Third, it will be determined whether mice deficient in beta-1, beta-2, or both beta-1 and beta-2 adrenergic receptors exhibit altered behavior under a differential-reinforcement-of-low-rate (DRL) schedule, compared to wild-type controls. Also, it will be assessed whether these genotypes of mice under this schedule respond differentially to beta adrenergic agonists and antidepressant drugs. Completion of the proposed experiments will demonstrate the roles that central beta-1 and beta-2 adrenergic receptors play in mediating depression-related behavior and antidepressant activity. This will lead to the better understanding of pathophysiology and pharmacotherapy of depression.